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• W1998310995 abstract "The article by Marion Wencker et al in this issue ofCHEST (see page 737) fits another piece with in the yet-unfinished jigsaw puzzle of the pathophysiology and treatment ofα1-antitrypsin (AAT) deficiency. The molecularand cellular mechanisms leading to this deficiency are among the bestunderstood of the genetic conditions leading to an increased risk fororgan dysfunction. The single amino-acid substitution seen in the mostcommon form of AAT deficiency leads to an altered conformation of thisprotein as it is translated in the hepatocyte.1Perlmutter DH Misfolded proteins in the endoplasmic reticulum.Lab Invest. 1999; 79: 623-638PubMed Google Scholar Thisprovokes insertion of the reactive loop of one Z mutation AATmolecule into the A-sheet of another Z mutation AAT molecule, resultingin polymerization and accumulation of AAT with in the hepatocytecytoplasm.2Lomas DA Loop-sheet polymerization: the mechanism of α1-antitrypsin deficiency.Respir Med. 2000; 94: S3-S6Abstract Full Text PDF PubMed Scopus (85) Google Scholar This, in turn, leads to the characteristicperiodic acid-Schiff-positive, diastase-resistant hepatocytegranules and a low serum level of this important serine proteinaseinhibitor. Lowered levels of AAT bathing the lungs leads to the possibility of connective tissue degradation by phagocyte proteinases, normally inhibited by physiologic concentrations of AAT.3Janoff A Proteases and lung injury: a state-of-the-art minireview.Chest. 1983; 83: 54S-58SPubMed Google ScholarThe insights gained from studying AAT deficiency have provided the basis for our growing comprehension of the mechanisms leading to COPDin general. Despite this understanding of the basic pathophysiologic mechanisms, ithas been difficult to design studies testing the treatment of thisdisorder. While the prevalence of AAT deficiency in US and Europeancommunities is relatively high (as many as 100,000 individuals on eachcontinent), only approximately 6% of affected individuals have beenidentified to date. Thus, large randomized trials become difficult toenroll. IV augmentation therapy using pooled human plasma AAT(Prolastin; Bayer Biologics; Research Triangle Park, NC) was approvedin the United States and several European countries approximately 10years ago. This approval was based on “biochemical efficacy”: the replacement of a deficient serum protein. The presence of awell-accepted the rapeutic option makes the implementation of placebo-controlled trials of clinical efficacy problematic. The article by Wencker at al attempts to evaluate the clinical efficacyof pooled human plasma AAT therapy using a multicenter, retrospectivetrial design, evaluating the same patients both before and afterinitiation of therapy. Previous studies from this group and from the United States National Institutes of Healthα1-Antitrypsin Deficiency Registry had detecteda decrease in the rate of decline of FEV1 and improved mortality in treated individuals whose lung function wasmoderately impaired. The current study of 96 patients showed astatistically significant lower rate of decline of FEV1 in the whole group during augmentationtherapy compared with the pretreatment period. The mean difference inrate of decline was 14.9 mL/yr. Interestingly, there was not asignificant difference in the pretreatment-posttreatment rate of decline (−3.7 mL/yr) in 25 patients with FEV1< 30% predicted. The difference in pretreatment-posttreatment rateof decline was larger (11.6 mL/yr) but not statistically significant in60 patients with FEV1 30 to 65% predicted. Thepretreatment-posttreatment rate of decline was greatest (73.6 mL/yr)and statistically significant in 11 patients with FEV1 > 65% predicted. Seven patients with arapid decline of FEV1 during the pretreatmentperiod with in the last group had a pretreatment-posttreatmentaugmentation therapy difference in FEV1 rate of decline of 203 mL/yr; four slow decliners showed a difference of−26.4 mL/yr. One study4Blank CA Brantly M Clinical features and molecular characteristics of α1-antitrypsin deficiency.Ann Allergy. 1994; 72: 105-120PubMed Google Scholar has suggested that the rapid decline inlung function seen in AAT-deficient individuals does not follow astraight line or smooth curve but, rather, proceeds in a stepwisefashion with each drop associated with a lung infection or otherinflammatory process. Using the pooled information of availablestudies1Perlmutter DH Misfolded proteins in the endoplasmic reticulum.Lab Invest. 1999; 79: 623-638PubMed Google Scholar5Survival and FEV1decline in individuals with severe deficiency of α1-antitrypsin: the α1-Antitrypsin Deficiency Registry Study Group.Am J Respir Crit Care Med. 1998; 158: 49-59Crossref PubMed Scopus (434) Google Scholar6Seersolm N Wencker M Banik N et al.Does α1-antitrypsin augmentation therapy slow the annual decline in FEV1in patients with severe hereditary α1-antitrypsin deficiency?.Eur Respir J. 1997; 10: 2260-2263Crossref PubMed Scopus (267) Google Scholar leads to a potential profile of the appropriate AAT-deficient patient to treat with augmentation therapy:one with moderately severe obstructive lung disease, or one with well-preserved lung function but early evidence of a rapid decline. Theutility of treating AAT-deficient patients with advanced COPD remainsunproven; the results of the current study in 25 patients with initialFEV1 values < 30% predicted suggest thataugmentation therapy is not worthwhile. However, this is aretrospective study, and the results may therefore be biased. As recently as 1 year ago, pooled human plasma AAT was in short supplyin the United States, with individuals with newly diagnosed conditionsprecluded from initiating therapy; those already receiving therapy wereforced to reduce their doses to amounts likely to be ineffective. Asthese patients changed location, physician, or insurance, they wouldfind the mselves unable to receive the drug. These problems have beenlargely eliminated since November 1, 1999, by an important and uniquedrug distribution method: direct patient allocation (Bayer Direct). Under this system, the drug is distributed directly to each patient and the allocation follows the patient regardless of changes in insuranceor location. Another clinical problem of growing magnitude, and which bearsimportantly on developing screening programs forα1-antitrypsin deficiency, is the concernregarding potential genetic discrimination in hiring and insurance. While the gene frequency of AAT-deficient alleles is approximately 21million individuals in the United States, this condition is stillconsidered quite rare by the practicing physician. Just as large-scaledetection efforts were being developed, an appreciation of geneticdiscrimination issues led to a tabling of these efforts. Untillegislative and regulatory proscriptions against such discriminationare in place, the efforts to increase detection of this geneticcondition will be thwarted. Regardless, it is anticipated that even the current, relatively meager detection efforts will lead to a worldwideshortage of augmentation therapy in the near future. In the late 1980s, we congratulated ourselves for having “solved” the riddle of AAT deficiency and its treatment in a mere 25 years. Now, in this new millennium, we see that our celebrations may have been abit premature." @default.
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• W1998310995 title "α1-Antitrypsin Deficiency Therapy" @default.
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